A tubulin alpha 8 mouse knockout model indicates a likely role in spermatogenesis but not in brain development

Tubulin alpha 8 (Tuba8) is the most divergent member of the highly conserved alpha tubulin family, and uniquely lacks two key post-translational modification sites. It is abundantly expressed in testis and muscle, with lower levels in the brain. We previously identified homozygous hypomorphic TUBA8...

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Published in:	PloS one 2017-04, Vol.12 (4), p.e0174264
Main Authors:	Diggle, Christine P, Martinez-Garay, Isabel, Molnar, Zoltan, Brinkworth, Martin H, White, Ed, Fowler, Ewan, Hughes, Ruth, Hayward, Bruce E, Carr, Ian M, Watson, Christopher M, Crinnion, Laura, Asipu, Aruna, Woodman, Ben, Coletta, P Louise, Markham, Alexander F, Dear, T Neil, Bonthron, David T, Peckham, Michelle, Morrison, Ewan E, Sheridan, Eamonn
Format:	Article
Language:	eng
Subjects:	Acetylation Acetyltransferase Actin Adhesion Adhesive bonding Alanine Amino acid sequence Amino acids Analysis Anatomy Androgens Animals Axon guidance Biology Biology and Life Sciences Biomedical materials Brain Brain - embryology Carbendazim Cell adhesion molecules Cell migration Cerebrum Coding Colchicine Cyclin-dependent kinase Cyclin-dependent kinase 5 Cytoskeleton Dominant traits Exome Exons Fragmentation Functional analysis Gene expression Genetics Homozygote Hypoplasia Infertility Isoforms Libraries Medical research Medicine Medicine and Health Sciences Mice Mice, Knockout Microtubules Mitosis Modulation Mutation Neurobiology Pharmacology Physiological aspects Physiology Position (location) Post-translational modification Post-translational modifications Protection and preservation Protein expression Proteins Rats Research and Analysis Methods Rodents Spermatogenesis Spermatogenesis - genetics Stability Synteny Tissues Tubulin Tubulin - genetics Tubulins
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Summary:	Tubulin alpha 8 (Tuba8) is the most divergent member of the highly conserved alpha tubulin family, and uniquely lacks two key post-translational modification sites. It is abundantly expressed in testis and muscle, with lower levels in the brain. We previously identified homozygous hypomorphic TUBA8 mutations in human subjects with a polymicrogyria (PMG) syndrome, suggesting its involvement in development of the cerebral cortex. We have now generated and characterized a Tuba8 knockout mouse model. Homozygous mice were confirmed to lack Tuba8 protein in the testis, but did not display PMG and appeared to be neurologically normal. In response to this finding, we re-analyzed the human PMG subjects using whole exome sequencing. This resulted in identification of an additional homozygous loss-of-function mutation in SNAP29, suggesting that SNAP29 deficiency, rather than TUBA8 deficiency, may underlie most or all of the neurodevelopmental anomalies in these subjects. Nonetheless, in the mouse brain, Tuba8 specifically localised to the cerebellar Purkinje cells, suggesting that the human mutations may affect or modify motor control. In the testis, Tuba8 localisation was cell-type specific. It was restricted to spermiogenesis with a strong acrosomal localization that was gradually replaced by cytoplasmic distribution and was absent from spermatozoa. Although the knockout mice were fertile, the localisation pattern indicated that Tuba8 may have a role in spermatid development during spermatogenesis, rather than as a component of the mature microtubule-rich flagellum itself.
ISSN:	1932-6203 1932-6203